Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are agents that are used to block the action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP. Currently, the PDE5 inhibitors sildenafil, tadalafil, and vardenafil are clinically indicated for the treatment of erectile dysfunction, while sildenafil and tadalafil are also indicated for the treatment of pulmonary hypertension.
Nitric Oxide Synthase (NOS) in endothelial cells converts L-arginine to L-hydroxyarginine and subsequently to nitric oxide (NO) and L-citrulline (FIG. 1 and FIG. 2). NO mediates its biological effects by activating guanylyl cyclase and increasing cyclic GMP synthesis from GTP which leads to the regulation of several biological processes such as vasodilation. 2 L-citrulline molecules combine to generate L-arginine to boost the NO generation cycle. NO exerts its biological action on smooth muscle by increasing cGMP which leads to vasodilation and increased blood flow in the genitals.
Vesele® (dietary supplement) is a dietary supplement designed to maximize the benefits of NO. It contains the amino acids L-citruline and L-arginine, as well as BioPerine® (extract), a piperine (FIG. 3) extract that helps the body absorb the amino acids (see U.S. Pat. No. 5,536,506 and European Patent EP0810868B1). BioPerine® (extract) inhibits human CYP3A4 and P-glycoprotein enzymes. By inhibiting certain enzymes BioPerine® (extract) may alter the effectiveness of certain medications by increasing bioavailability. For men, daily consumption of Vesele® (dietary supplement) provides a significant improvement of erection hardness and maintenance, frequency of intercourse with partner and partner satisfaction as well as an overall satisfaction with sexual health. Women taking Vesele® (dietary supplement) have documented a significant satisfaction in lubrication, sexual desire, ability to be aroused and frequency of intercourse with partner.
In spite of the commercial success that sildenafil, tadalafil, and vardenafil have enjoyed, 50% of all patients stop using these drugs due to the lack of effect on erection and especially on penis hardness and maintenance to allow a successful vaginal penetration and ejaculation. There is currently a need for compositions and methods that are effective to improve and maintain NO production in vivo and/or to increase NO levels in blood to maintain an erection and maintain the hardness of the penis. There is also a need for improved compositions and methods that are effective to treat erectile dysfunction to continue to allow patients to respond properly to current treatments